At present a whole range of compounds possessing antiviral activity against HIV are used in practical medicine. They include nucleoside and non-nucleoside inhibitors. The most frequently used nucleoside derivatives include 3′-azido-3′-deoxythymidine (AZT, Zidovudine), 2′,3′-dideoxycytidine (ddC, Zalcitabine, 2′,3′dideoxyinosine (ddI, Didanosine), 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T, Stavudine and 2′,3′-dideoxy-3′-thiacytidine (3TC, Lamivudine) [De Clercq, E., 2002. New development in anti-HIV chemotherapy. Biochim. Biophys. Acta, 1587 258-275].
The mechanism of action of the above compounds comprises its diffusion into infected cells, where they undergo triphosphorylation and specifically inhibit DNA synthesis catalyzed by HIV reverse transcriptase. High variability of HIV results in rapid emergence of resistant strains of the virus [Groschel, B., Cinatl, J. H., and Cinatl J. Jr., 1997. Viral and cellular factors for resistance against antiretroviral agents. Intervirology, 40, 400-407; Antonelli, G, Turriziani, O., Verri, A., Narciso, P., Ferri, F., D'Offizi, G., and Dianzini, F., 1996. Long-term exposure to zidovudine affects in vitro and in vivo the efficiency of thymidine kinase. AIDS Res Hum Retrovir., 12, 223-228] and, hence to the necessity of changing medication. Besides, due to low efficacy of intracellular transformations currently used drugs have to be administered in high doses leading to pronounced toxic effects.
AZT toxicity causes suppression of the activity of spinal cord cells, liver function impairment and myopathy [Chariot, P., Drogou, I., De Lacroix-Szmania, I., Eliezer-Vanerot, M. C., Chazaud, B., Lombes, A., Schaeffer, A., and Zafrani, E. S., 1999. Zidovudine-induced mitochondrial disorder with massive liver steanosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J. Hepatol. 30, 156-160; Kellam, P., Boucher, C. A., and Larder, B. A., 1992. Fifth mutations in HIV reverse transcriptase contributes to the development of high level resistance to zidovudine. Proc. Natl. Acad. Sci. U.S.A, 89, 1934-1938; Ren, J., Esnouf, R. M., Hopkins, A.L.,  Jones, E. Y., Kirby, I., Keeling, J., Ross, C. K., Larder, B. A., Stuart, D. I., and Stammers, D. K., 1998. 3′-Azido-3′-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes. Proc. Natl. Acad. Sci. U.S.A, 95, 9518-9523]. Rapid elimination of AZT from the body necessitates frequent administration. Besides, resistant strains of the virus develop rather soon during long-term treatment with AZT and the therapy loses its efficacy. Despite all the above disadvantages AZT still remains the most widely used anti-HIV drug.
The known H-phosphonate of AZN (Nikavir®) approved for AIDS treatment in Russia is less toxic than AZT [Intracellular metabolism and pharmacokinetics of 5′-hydrohenphosphonate of 3′-azido-2′,3′-dideoxythymidine, a prodrug of 3′-azido-2′,3′-dideoxythymidine. Antiviral Research 63 (2004), 107-113]. The effect of Nikavir is based on its ability to release AZT which, after intracellular transformation to AZT-5′-triphosphate inhibits the replication of HIV. According to pharmacokinetic research data, clinical advantages of Nikavir are due to slower and more gradual increase of AZT concentration in the blood than in case of administration of proper AZT; Cmax of AZT from Nikavir being less than Cmax of AZT from Zidovudine, and T1/2 of AZT from Nikavir being greater than T1/2 of AZT from Zidovudine [Y. Skoblov et al./Antiviral Research 63 (2004) 107-113]. Nevertheless, the toxicity of Nikavir remains rather high. Another disadvantage consists in the development of resistance to Nikavir.
Some other AZT derivatives were synthesized and evaluated as anti-HIV agents. Among them there are 5′-alkylphosphonyl AZT (alkyl is C1 to C8) [A. A. Kraevsky et al W091/19727 and N. S. Bodor W092/00988], 5′-fluoromethylphosphonyl, 5′-difluoromethylphosphonyl, 5′-fluorocloromethylphosphonyl- and 5′-trifluoromethylphosphonyl-AZT [P. J. Casara et at Biorganic Med. Chem. Letters, 2(2) (1992) 145-148]. Earlier physicochemical properties of 5′-hydroxymethyl- and 5′-iodomethylphosphonyl AZT were reported [V. M. Orlov et al, Molekulayrnaya Biologia (Moscow), 28(3) (1994) 708-713]. In addition, chemical synthesis of 5′-R-phosphonyl-AZT where R═—H2C(O)NH2, —C(O)NH2, —C(O)NHCH3, —C(O)NHCH2CH2Ph,
was described [E. A. Shirokova et al, Nucleosides, Nucleotides&Nucleic Acids 22(5-8) (2003) 981-985; E. A. Shirokova et al, Russian Journal of Bioorganic Chem. 30(3) (2004) 242-249; E. A. Shirokova et al, J. Med. Chem. 47(14) (2004) 3606-3614.], however their biological properties were not studied.